title: In vivo profiling of DPP4 inhibitors reveals alterations in collagen metabolism and accumulation of an amyloid peptide in rat plasma.
abstract: Dipeptidyl peptidase 4 (DPP4) inhibitors represent a novel class of oral anti-hyperglycemic agents. The complete pharmacological profile of these protease inhibitors remains unclear. In order to gain deeper insight into the in vivo effects caused by DPP4 inhibition, two different DPP4 inhibitors (vildagliptin and AB192) were analyzed using differential peptide display. Wistar rats were treated with the DPP4 inhibitors (0.3mgkg(-1); 1mgkg(-1) or 3mgkg(-1) body weight) and DPP4 activity was measured before and at the end of the experiment. One hour after compound administration, blood plasma samples were collected to generate peptide displays and to subsequently identify differentially regulated peptides. A dose-dependent decrease in blood plasma DPP4 activity was measured for both inhibitors. DPP4 inhibition influenced collagen metabolism leading to depletion of collagen derived peptides (e.g. collagen alpha 1 (III) 521-554) and accumulation of related N-terminally extended collagen derived peptides (e.g. collagen alpha 1 (III) 519-554). Furthermore, the intact amyloid rat BRI (1-23) peptide was detected in plasma following in vivo DPP4 inhibition. DPP4 catalyzed cleavage kinetics of the BRI peptide were determined in vitro. The k(cat) and K(m) for cleavage by DPP4 were 5.2s(-1) and 14microM, respectively, resulting in a specificity constant k(cat)/K(m) of 0.36 x 10(6)s(-1)M(-1). Our results demonstrate that differential peptide analysis can be applied to monitor action of DPP4 inhibition in blood plasma. For the first time effects on basal collagen metabolism following DPP4 inhibition in vivo were demonstrated and the BRI amyloid peptide was identified as a novel DPP4 substrate.
authors.affiliation: Digilab BioVisioN GmbH, Hannover, Germany.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Jost
authors.forename: Jens
authors.initials: J
authors.lastname: Lamerz
authors.forename: Harald
authors.initials: H
authors.lastname: Tammen
authors.forename: Christoph
authors.initials: C
authors.lastname: Menzel
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lambeir
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
authors.forename: Simon
authors.initials: S
authors.lastname: Scharpé
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Zucht
authors.forename: Horst
authors.initials: H
authors.lastname: Rose
authors.forename: Michael
authors.initials: M
authors.lastname: Jürgens
authors.forename: Peter
authors.initials: P
authors.lastname: Schulz-Knappe
authors.forename: Petra
authors.initials: P
authors.lastname: Budde
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000682:Amyloid / Q000097:blood*; D000818:Animals; D003094:Collagen / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000097:blood* / Q000737:chemistry / Q000302:isolation & purification; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D006352:Heart Ventricles / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D009570:Nitriles / Q000494:pharmacology*; D063065:Organophosphonates / Q000494:pharmacology*; D010446:Peptide Fragments / Q000097:blood* / Q000302:isolation & purification; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013379:Substrate Specificity; D000077597:Vildagliptin
chemical_list: D000682:Amyloid; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D063065:Organophosphonates; D010446:Peptide Fragments; D011759:Pyrrolidines; C118220:bis(4-acetamidophenyl) 1-prolylpyrrolidine-2-phosphonate; D003094:Collagen; D011392:Proline; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane